The Protective Effect of Fenofibrate Against TNF-α-Induced CD40 Expression through SIRT1-Mediated Deacetylation of NF-κB in Endothelial Cells

Abstract

Fenofibrate, as a lipid-lowering drug in clinic, participates in the regulation of inflammatory response. Recently, increasing studies have indicated that sirtuin1 (SIRT1), a NAD+-dependent deacetylase, has potential anti-inflammatory effect in endothelial cells. However, whether the regulatory effect of fenofibrate on inflammation response is mediated by SIRT1 remains unclear. The aim of this study was to investigate the effect of fenofibrate on the expressions of SIRT1 and pro-inflammatory cytokine CD40 in endothelial cells and explore the underlying mechanisms. The results showed that fenofibrate upregulated SIRT1 expression and inhibited CD40 expression in TNF-α-stimulated endothelial cells, but these effects were reversed by peroxisome proliferator-activated receptor-α (PPARα) antagonist GW6471. Furthermore, SIRT1 inhibitors sirtinol/nicotinamide (NAM) or SIRT1 knockdown could attenuate the effect of fenofibrate on CD40 expression in endothelial cells. Importantly, NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) augmented the effect of fenofibrate on CD40 expression. Further study found that fenofibrate decreased the expression of acetylated-NF-κB p65 (Ac-NF-κB p65) in TNF-α-stimulated endothelial cells, which was abolished by SIRT1 knockdown. These results indicate that fenofibrate has protective effect against TNF-α-induced CD40 expression through SIRT1-mediated deacetylation of the p65 subunit of NF-κB.

Protectin DX ameliorates palmitate- or high-fat diet-induced insulin resistance and inflammation through an AMPK-PPARα-dependent pathway in mice

“…Fenofibrate, a well-known agonist of PPARα, ameliorates the IL-1-induced inflammatory response in human aortic smooth muscle cells by inhibiting IL-6 expression 32 and reduces plasma triglyceride with a concomitant increase in high-density lipoprotein-cholesterol in humans with metabolic syndrome 16 . Furthermore, fenofibrate shows protective effects against TNFα-induced inflammation via sirtuin1 (SIRT1)-associated inhibition of NFkB activity in endothelial cells 33 . Fatty acid oxidation and energy consumption resulting from PPARα activation in skeletal muscle and adipose tissue has many beneficial effects, including improved exercise endurance, insulin sensitivity, and reduced body weight 17, 19, 20 .…”

Hugan QingzhiExerts Anti-Inflammatory Effects in a Rat Model of Nonalcoholic Fatty Liver Disease

“…Cao et al demonstrated that amyloid beta- (A β -) induced IL-8 and IL-6 expression was attenuated in cells pretreated with SIRT1 activators and that SIRT1 knockdown exacerbated the A β -induced proinflammatory effects [46]. Recently, several studies have shown that fenofibrate exerted protective effects against TNF- α -induced CD40 expression through SIRT1-mediated deacetylation of the NF- κ B-p65 subunit [47]. Similarly, we have found that fenofibrate and HQT (HM/HH groups) increased SIRT1 and decreased Ac-NF- κ B-p65, TNF- α , IL-1 β , and IL-6, which suggests that the beneficial effect of HQT on anti-inflammation might be partly attributable to the upregulated expression of SIRT1.…”

miR-23b-3p induces the cellular metabolic memory of high glucose in diabetic retinopathy through a SIRT1-dependent signalling pathway

“…It regulates cellular inflammation in endothelial cells, and the anti-inflammatory property of SIRT1 is closely related to its inhibition of NF-κB [11][12][13].…”